Note: In this article Dr. Donaldson addresses the concept of death as a collection of disease states which are beyond treatment by the medicine of a particular era. The cultural significance attached to pronouncements of death obscures the fact that many conditions called "death" in fact consist of specific pathologies that could be treatable by medicine of future eras. Patients considered dead in one era may be not be dead in another. This suggests the need for a more absolute biological definition of death, motivating the concept of "information theoretic death" several years after publication of this article.

Prospects of a Cure for "Death"

by Thomas Donaldson, Ph.D.

Of course you probably recognize that the title is a misnomer for the same
reason an article about a cure for cancer is a misnomer. There are so many different
varieties of cancer, and so many different varieties of death, that no one cure
can exist. But since there is so much optimism about curing cancer, and so little
optimism about curing death, the title begins by bringing out the parallels.

We will probably always have some form of death, and some form of cancer. Looking
at cancer, of course, most people see this optimistically: "yes, but many forms
will disappear." Death, however, is an "eternal verity" and the "proper" attitude
is to concentrate on the deaths that remain rather than those that disappear.
For cancers, the absence of any single overriding cure is something to regret
as a man of the world. For deaths, it is one more proof of an eternal verity.

No short article can do justice to the problems of cures for death because
there are too many kinds of death, each needing a separate cure. What I will
do, when I become technical, is to discuss a few currently major types of death
and prospects for their cure. But we ought not to become technical too soon,
because that's a very good way not to see the forest for the trees.

Fundamentally, cryonic suspension isn't about freezing people whose conditions
are clearly just a matter of time until we find a technology to deal with them.
It's about freezing people whom we don't know how to cure or even if a cure
will be possible. Someday almost certainly we'll have better means to preserve
people, too. Freezing is only our current best means. But cryonics is about
preservation, the need for which will always remain.

Right now, nanotechnology has become a popular idea. But nanotechnology only
solves half the problem, that of manipulating life on very small scales. The
other half, whether there is a patient there to be saved, isn't yet known. Probably
it will never be known for all patients in all conditions. We didn't need nanotechnology
before to tell us that cryonic suspension was right. We don't need it now, either.
It is right to keep people around in suspension because cures for their problems
have a way of turning up. We should not let ourselves be turned into fertilizer
just because we don't see how we can be fixed. Doing that isn't just wrong,
it is absurd. And so, nanotechnology is a proof of cryonics, but in a deeper
way. You thought, before, that no possible way could repair frozen people. And
now, somebody has come up with a possible way. See, you've just seen it happen:
cures for their problems have a way of turning up. (Didn't you hear me the first
time?)

There's another fundamental point, put forward first by Robert Ettinger. It
is actually a technical point, so I will discuss it later. But it isn't really
a point about particular technologies or particular knowledge. Watch for it.

Ischemia and hypoxia

The two deaths I shall discuss are closely related. They often happen as the
final outcome of many other conditions, such as cancer or heart disease. When
a person's heart stops for any reason, his brain suffers ischemia, which
means "absence of blood flow." If blood flow stops to any particular brain region,
we have local ischemia, which if it continues long enough causes a stroke. If
it only lasts a short time (perhaps a few minutes) then people can recover.
But they will have felt a transient loss of control over one side of their body,
or a transient loss of memory, or other temporary brain problem. (If this happens
to you, go to a doctor at once!)

Hypoxia (literally: "low oxygenation") is a condition in which only
small amounts of oxygen reach the brain (or other organs). It can result from
suffocation, which in turn can result from emphysema, chronic bronchial obstruction,
severe asthma, or other conditions. If allowed to continue, it often continues
into ischemia, but it is quite damaging in itself.

Legal declaration of death usually occurs after ischemia has lasted for more
than four minutes. Usually, though, ischemia isn't the reason for declaration
of death. Attending doctors had already decided not to revive the patient if
his or her heart stopped. Brain ischemia just ratifies their decision.

Cellular and biochemical events of ischemic death

For cryonics, the relevant events of ischemic death all happen before anyone
tries to restore circulation. Many neurologists have reported their observations
of what happens after attempts to restore circulation. These reports all describe
a slow (over a period of many hours) deterioration of neurons into fragments
of cells. We should see this deterioration as a consequence of ischemic death
rather than identical to it.

These observations are very important for anyone trying to cure ischemic death.
Sometimes they also tell us indirectly about the events which happen during
ischemia. But even only a short time after we attempt to restore circulation,
our brain cells end in far worse condition than immediately after ischemia.
The papers I discuss in Box 1 attempt to work out, through observations during
and after ischemic death, just what happens in that time.

Box 1: Injuries to circulation and support

Brains are complex systems. Ischemia injures much more than just their
neurons. Without supposing any immediate damage at all to neurons, these
injuries can alone explain a lot of brain damage after ischemia.

The major event after ischemia, and historically the earliest one seen,
is swelling and blocking off of the capillaries. Attempts to restore circulation
therefore fail and hours later the neurons themselves will die. Some papers
observing these changes are:

Given that after ischemia, swelling of brain capillaries cuts off support
for the neurons, we would like to know just how functional are the neurons
themselves. One way to find this out consists of treating the brain to
restore circulation. In 1969 K. A. Hossmann and K. Sato at the Max Planck
Institute tried this with cats. They could show recovery of neurons after
as long as one hour of ischemic death at room temperature. (Then and now,
brains aren't thought to live past about five minutes of ischemia). Some
papers describing Hossmann and Sato's work are:

For ischemia and hypoxia, current technology can recover people from these
deaths, if the incidents don't last more than about four minutes. Some studies
have even claimed as long as 15 minutes for patients at room temperature.

Cryonics patients will usually follow a different course. But even for cryonicists,
accidents or neglect can cause quite prolonged delay. Heartbeat can stop minutes
or hours before a suspension team can reach the patient. Cures for ischemic
and hypoxic death remain extremely important to us.

Curable in principle and curable in fact

Even if only a few scraps of skin are left, we can in principle recreate a
whole human being from those scraps. That created or recreated person would
remember nothing of what their forerunner had done, believed, or wanted. They
would be twins of their original. Re-creation or creation of this kind may in
fact become common. When both John and his friends want to hang on to continuity,
they could create someone with no memories at all from any scraps of John remaining,
and declare that recreated person to be John. Of course, they will say that
John was "hurt so badly in his accident that he lost all his memories."

But this is philosophy. Such a re-creation isn't what we want. We want to come
back with our memories, beliefs, and ambitions intact. If this isn't possible,
we want to come back with as much as possible. In discussing cures for death
we must therefore discuss just how much damage the different deaths do to our
memories and character.

Events during brain ischemia

Twenty years ago, most neurologists thought that after four minutes of ischemia,
patients followed an inexorable downward course. One very important scientific
development of the last 20 years consists of a growing realization that this
isn't so, that drug treatments can alter the sequence of events after ischemia.
Ischemia deaths (and strokes, which are ischemia deaths of only a part of the
brain) are now problems to be worked on rather than decrees of omnipotent gods.
However, official neglect and many accidents produce conditions identical to
those of 20 years ago. I'll therefore begin by discussing what we know of as
happening during ischemic death.

The most outstanding fact about ischemic or hypoxic death is that, so far as
current experiments tell, most damage occurs after circulation is restored.
Very few papers have studied what happens to brain cells if nobody tries to
revive the patient. For cryonics this is very important. We're not trying to
revive the patient in the near future. We're just trying to freeze them with
as little additional cellular damage as possible. The problem of bringing them
back is left to a technology far better able to deal with all the pathologies
that happen after attempted revival.

A small amount of work does try to delimit events during ischemia. Furthermore,
the damage happening with revival really happens because of groundwork for it
laid down during ischemia. We can use this work to infer what has happened during
ischemia. In Box 1, I have set out some kinds of events known to occur in the
ischemic brain. Hypoxia is more serious because even if only a little oxygen
gets through to the brain, the biochemical events involved can cause damage
even while hypoxia goes on.

How reversible are ischemic changes?

The most direct way to show survival of neurons after ischemia would be to
grow them in culture. Unfortunately, few neurologists have bothered to do culture
studies of adult neurons taken from postmortem patients.

Even after an hour of ischemia, brain cells go through many structural changes.
But cells aren't mechanical systems. Many dramatic changes in cell structure
completely reverse when we restore oxygen and nutrients. Cell cultures can tell
us just how serious these changes may be.

From what little we know of memory storage, these changes don't involve outright
destruction of memory. To try to evaluate this, we can look closely at the effects
of ischemia on two parts of the cell probably involved in memory: the cell nucleus
and the synapses.

One fundamental form of damage consists of damage to the cell's ability to
make new proteins. This may happen in the nucleus, where the initial stages
of making new proteins occur. But several stages equally critical happen outside.
The machinery to synthesize a protein is very complex: the cell reads off plans
for the protein from the genes onto RNA, which then moves to the ribosomes,
which make the actual protein. We don't know which part of this machinery is
damaged and which remains. A major point, though, is simply that this is machinery.
It isn't just a single molecule which can be destroyed or not. This complexity
suggests that evidence of memory will remain despite damage.

Few scientists have studied events within the cell nucleus during and after
ischemia. Much more attention has gone into means to prevent its effects prior
to the event. Alcor itself has devoted considerable attention to that problem,
with some success. But that's a significantly different problem.

Yanigihara reports experiments which study the binding of ATP to proteins within
the cell nucleus. ATP is a common form of energy storage for all cells. Both
during and after ischemia, some high molecular weight proteins in the cell nucleus
lose their ability to bind to ATP. Since the nucleus needs ATP to make new protein,
this change may explain the failure of protein synthesis after ischemia. Failure
to bind to ATP happens to some quite specific proteins with molecular weights
about 60,000 times that of a single hydrogen atom. Since the nucleus contains
many different kinds of protein, we have no reason to believe this protein encodes
for neuron memories.

Synapses may also carry memory. Ischemia damages all cell membranes, and so
also the cell membranes of the synapses. The damage consists of chemical reactions
which destroy phospholipids, one characteristic component of the cell membranes.
These components are unlikely to carry memory, especially because they occur
not just at synapses but everywhere in cell membranes.

Box 2 covers some papers on the culture of brain cells.

Box 2: Neuronal cell culture

Some reports of neuron cell cultures taken from postmortem human patients
are:

Kim and his coworkers successfully cultured human neurons from the spinal
cord (the superior cervical ganglion from the neck) taken from adults
between four and six hours after death. They point out "with surprise"
that they could succeed even after so long a delay after death.

Retinas from five dogs, taken within one hour after death, survived in
culture. The retina is an extension of central nervous tissue. I believe
we may accept that neurons will definitely survive one hour of ischemia.
No attempts to culture dog neurons taken after one hour are reported.

This is an example of an earlier paper, in which cell cultures from cadaver
brains are established as long as six hours postmortem. The authors report
the rare presence of cells which appear to be neurons.

Establishing a cell culture of adult neurons is very difficult. Neurologists
only developed reproducible procedures as late as 1979. Furthermore, cultured
cells can lose the characteristic shapes by which we know them in living
animals. The meaning of earlier reports therefore isn't clear. I have
not found any recent attempt to culture neurons taken from the cerebrum
of adult human beings postmortem.

The points to be made from these experiments are:

Brain cells, and therefore brains, may be essentially viable for up to six
hours at room temperature. We urgently need to repeat and expand upon the
work on culturing brain cells taken from adult brains after death. Few scientists
have even tried to do this, but their results are very suggestive. Up to six
hours, also, brain cells retain their structure very well. Changes at the
microscopic level, and even at the electron microscopic level, are relatively
small.

For up to six hours, repair probably won't require any advanced nanotechnology.
At its low end, of course, nanotechnology shades into ordinary pharmacology.
Many changes in brain cells during ischemia are changes in levels of crucial
chemicals such as calcium ions. Drugs which sequester these should cause a
distinct improvement (and do). Other events such as destruction of membrane
phospholipids may require activation of systems to rebuild membranes. Since
brain cells already tear down and rebuild membranes constantly, drugs only
need to protect and enhance this ability, not reproduce it artificially.

One problem with current drugs may be that they act on too many different chemistries.
Designer drugs with much more specific action, capable of entering brain cells,
should help this problem a good deal. One system a step beyond our current abilities
might consist of an interrelated family of drugs, activated only in specific
circumstances, and controlling one another's action much like enzyme systems
do in normal biochemistry. Systematic modification of existing enzyme systems
is one road to making such systems.

Not in all cases. . . .

How, then, would we go about repair of ischemic brain? One point Robert Ettinger
made 20 years ago still stands, and is quite profound. In The Prospect Of
Immortality, Bob made the comment that brain cells after ischemia (or freezing)
simply are not universally destroyed. Even in adult human beings, significant
areas of brain can survive lengthy periods of ischemia. What does that mean?
Bob described a column of soldiers after a machine gun attack. If none of the
soldiers ever gets up or shows any sign of life, then they've probably all been
killed. But if only a few get up afterward, then many more are probably wounded
but still alive.

Box 3: Reversible ischemic changes

As an illustration of changes known to reverse, a detailed study of ischemic
changes in brain neurons is:

After one hour of ischemia and under light microscopy, the neurons showed
slight swelling. Under electron microscopy, mitochondria were swollen,
the myelin sheath surrounding the nerves had begun to disintegrate, and
the nucleus underwent changes (chromatin in the nucleus had clumped together).
The Golgi bodies (characteristic bodies within neurons) swelled up "remarkably."
The cell matrix also lost chemicals, so that it seemed to become lighter
in the electron microscope. These changes were gradual and progressive
for up to 10 hours.

What this analogy argues is that brain cells after ischemia aren't grossly
disrupted. They are probably completely normal cells except for a very small
number of metabolic faults. Almost 20 years of neurological research lets us
go much farther to specify exactly what has happened to ischemic cells. This
tells us just what kinds of medical technology we need to repair them. Here
is a list of faults and specific suggestions for repair technologies:

Failure of protein synthesis

We don't currently know what links in the protein synthesis chain have been
disrupted. Only one link, of course, breaks the entire chain. To solve this
problem we must identify the wounded molecule, not individually for every cell
but by research into chemical events generally happening in ischemia. A properly
tailored enzyme, perhaps with a delivery system to inject it into the cell,
will deal with this molecule.

Box 4: Failure of protein synthesis

Another event occurring during ischemia has many consequences for neuron's
ability to recover afterward. For reasons not yet clear, the neurons lose
their ability to make new proteins. Since even minimal repairs of cell
damage require making new proteins, this loss virtually determines everything
afterward. The following papers report that this failure occurs and examine
its reasons:

Yanagihara's paper is particularly interesting. He found that certain
specific proteins in the cell nucleus changed their binding to ATP, the
cells' energy transfer chemical, after ischemia. He may have located the
problem to changes within the cell nucleus.

Membrane destruction

Normal cells maintain their own cell membranes. If injury to membranes is too
great, the cell cannot maintain its own internal composition. What is needed
here is a chemical system which can arrive from outside, carrying the needed
energy, and bringing with it much the same enzyme systems cells currently have
for membrane construction. An elaborate system isn't needed.

Reports of success with drugs like verapamil are very significant here, because
they suggest that after ischemia the structural parts of membranes still remain.
What may happen is that the cellular pumps which constantly work to maintain
chemicals within the cell are deranged. If true, then very much simpler strategies
than the above should work.

Box 5: Cell membrane changes

Loss of energy sources by the cell causes it to degrade its own membranes.
The entire membrane isn't destroyed outright. Instead, selected components
are. The following paper reports experiments on destruction of cell membranes
during ischemia:

Fatty chemicals, the phospholipids, form the basic structure of cell
membranes. Initial ischemia causes destruction of the one specific such
chemical, the phosphatidylinositols, in brain cell membranes. Arachidonic
and stearic acids result from this. Later, in a slowly progressing reaction
lasting many hours, other fatty chemicals making up the membrane are gradually
degraded.

Unfortunately, once the cell makes arachidonic and stearic acids, other
chemical reactions then make even more damaging chemicals out of them.
Among these are prostaglandins, thromboxanes, and leukotrienes.

One issue very important to us is damage to the synapses. Very few papers
look specifically at synapses. However, the following paper does:

Damage to synapses consists of cell membrane damage much like that of
other parts of the cell membrane. No special damage to synapses seems
to be involved.

Imbalances of calcium, sodium, and potassium within the cells

A specially designed enzyme system which simply sequestered these atoms, and
only worked within the cell, would repair this problem. It's possible that repairing
the pumping ability of the membranes would solve this problem too.

Box 6: Chemical imbalance within neurons

The most outstanding changes to neurons during ischemia come from changes
in their chemical balance. First, without oxygen or glucose, the cell
has no fuel. Cells aren't passive bags. They use energy constantly to
maintain a different concentration of chemicals inside than outside. Cell
membranes contain pumps constantly working to keep calcium outside and
potassium inside. Without energy, these pumps fail. Calcium enters the
cell, where it poisons the ability of the cell to produce energy. Calcium
also causes breakdown of the cell's membrane, which of course allows even
more calcium to enter. A review describing all of these events is:

Release of prostaglandins, leukotrienes, and other chemicals causing
swelling

This only happens after ischemia, and causes swelling which cuts off blood
flow to the brain. Any drug or other simple chemical system which deactivated
these substances (and any others like them which may be also be released) would
solve this problem. Repair after revival would consist of immediate provision
of this drug system.

Release of free radical chemicals

Just like the drugs which sequester calcium ions, a simple drug system to deactivate
these free radicals will answer to this problem.

Box 7: Free radical damage

Free radicals are damaging chemicals made when the cell burns its food.
Because of their role in aging, free radical damage is a very popular
hypothesis. For ischemia, though, the situation is cloudy. Neurologists
have disputed for the last 10 years about existence of free radical damage.
Two papers taking opposite sides in the dispute are:

Devices able to carry out these repairs are not advanced instances of nanotechnology.
One problem easy to neglect here, though, is simply that we must work out very
specifically just what the problem is before we repair it. This takes time.
Research will have to explore many different possible injuries before it finds
a very small number, maybe only one, of actual injuries. Nanotechnological devices
as research tools let us do much more sophisticated probing of cell injury.
We may still need many years to probe the problem.

It might easily happen (remember aspirin and heart disease?) that we discover
effective treatments which are simple, even banal. Yet we may have needed all
our nanotechnology to make this discovery.

What about after six hours?

For ischemia up to six hours duration, 20 years of research has taken us far
along the road to a solution. Reviving someone after six hours of ischemia simply
isn't a problem within the ken of today's research. Right now in 1990 we know
very little about what the injuries are. Ideas about repair are bound to change.

Still, we do know that cell membranes are seriously damaged. At some stage
the brain cells simply won't support piecemeal additions and metabolic helps.
A repair device would have to bring along its own genetic apparatus and protein
synthesizing machinery. We can envision these as resembling bacteria. Their
problem isn't really to recognize the damage and how to repair it. All of that
can be done from our preexisting understanding of cell reactions combined with
an ability to read off information from the target cell's own DNA. They will
need their own genetic and synthetic machinery because the target cell can't
provide any help on its own.

The first act of the repair cell would consist of rebuilding the target cell's
membranes and membrane pumps. It would then rebuild, clear out, or even replace
the target cell's mitochondria. By this time the target cell could start to
function on its own. The repair cell could withdraw, leaving behind a repair
system like that we've seen earlier.

Other damage

The preceding was an account of events during brain ischemia. The brain is
not quiescent. The neurons are frantically trying to adjust to many damaging
events. But they fail and cause even more damage by doing so. All of these events
set the stage for more damage after attempts to restore circulation.

It is only after circulation returns that blood vessels and glial cells swell
up to cut off circulation. Starved of energy, the neurons go into seizure activity,
which uses up even more energy and leaves them in a worse state. Because they
can't make more proteins, even normal metabolism wears them out and they slowly
die.

Of course, by intervening in these events we can expect to prevent or counteract
them completely.

Cell repair and cell technology

Death has many forms, ultimately each needing its own repair. Looking at only
one major form, ischemic, we find it consists of a series of events lasting
many hours and still only partly understood. During ischemia, more and more
cell damage progressively occurs, to an increasing number of specific sites
within a cell. Practical and real repair technologies will become sophisticated
along a gradual range. At the near end they would look simply like special designer
drugs, exactly the kind of drugs current pharmaceutical chemists invent. (The
only distinction is that these drugs will act on novel sites not yet known).
From single drugs, repair technology passes to interacting systems of drugs,
from there to viruslike systems with some capability of directed response. .
. and so on.

One major lesson of these ideas is of exactly how important gradual improvement
is and should be to any serious plan to cure any kind of "death." We should
not think of repair as a matter of fully sophisticated nanocomputers or nothing.
Indeed, not to take the first elementary steps with elementary nanomachines
(drugs, drug systems, gene transfer viruses) guarantees that advanced devices
will never come, ever. Seeds never planted never grow, no matter what technology
exists elsewhere.

A second lesson makes the point that we need to focus not just on the technology
needed for repair, but also on technology needed to find out how to repair.
Electron microscopes haven't yet directly cured anyone of any illness. Their
value lies elsewhere. Whenever we look specifically at some kind of death, the
first and major step consists of exploring the problem and its causes. Before
we find these causes, we must sift through fantastically many possible causes,
only one of which will turn into reality, every one of which is equally real
prior to our search. Once we find cures, all but one becomes forgotten history.
Any nanotechnological tools helping our search have immense value even if they
never come near a patient.

Finally
and ultimately, no one else will bring us cures for conditions that only we
consider as diseases instead of Theological Events. Not just the suspension
itself, but every stage along the way will come not from faceless Scientists
but from cryonicists and their own work. But then, we don't just have five minutes
but five CENTURIES in which to find these cures. Perhaps even five millennia.
Welcome, everyone, for your ride into history.